Resolved
Authors: Jonathan Himmelfarb, Lynda Anne Szczech
Journal: Journal of the American Society of Nephrology (2009)

Multiple studies document a consistent relationship between lower hemoglobin concentration and poorer outcomes in managing the anemia of chronic kidney disease (CKD) or anemia in dialysis populations.1–3 Additionally, many studies demonstrate an association between anemia treatment and reduction of left ventricular mass index.4,5 Because altered left ventricular geometry is a predictor of poor outcomes among dialysis patients,6 these studies suggest that treatment of anemia may translate into an improvement in cardiovascular events and mortality. However, large randomized trials of anemia correction in kidney disease using erythropoiesis-stimulating agents (ESAs) also report unexpected results.7–9 In particular, the Normal Hematocrit Trial and the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) studies demonstrate a trend or a statistically significant increase in the risk of cardiovascular events or death. These data have been interpreted as inconsistent with observational data, with post hoc suggestions that residual confounding and bias in observational datasets led to these discrepant findings. Herein, we argue that the important messages for anemia management in kidney disease are actually consistent across the spectrum of all available randomized clinical trials, including analyses of large observational datasets. These relationships are robust across multiple studies and across a large range of achieved hemoglobin concentrations. The two important messages are: First, the higher the achieved hemoglobin concentration, the better the patient outcome, at least up to a hemoglobin concentration of 13 g/dl, and second, the higher the ESA dose, the worse the patient outcome. The interpretation of randomized trial data and observational datasets only diverges when we introduce a third element, namely, the prescription of ESAs to a target hemoglobin concentration irrespective of patient characteristics. The concept of treating to a target hemoglobin concentration derives from the landmark Phase 1 to 2 single-center erythropoietin trials conducted over 20 yrs ago, which first established efficacy for erythropoietin in treatment of the anemia of kidney disease.10 These trials demonstrate a monotonic relationship among the erythropoietin dose, the trajectory of hemoglobin increase, and the achieved hemoglobin. The observed monotonic relationship suggests that erythropoietin deficiency is a dominant driver of anemia in kidney disease and, therefore, erythropoietin could be dose-titrated similar to other endocrine deficiency diseases. The corollary assumption is that the anemia of kidney disease is a relatively simple disease state. Thus, when erythropoietin received a Food and Drug Administration (FDA) label on the basis of the available data from these highly selected trial participants, it was reasonable to rely solely on a targeted hemoglobin concentration that would enhance quality of life and provide freedom from blood transfusions. Since then, the accepted anemia management paradigm is to treat to a target range. Indeed the FDA label, virtually all clinical practice guidelines published worldwide, and current clinical performance measures in the United States all still recommend dosing to a target hemoglobin concentration range. However, evidence that biologic response to erythropoietin is more varied in clinical practice appears as early as 1989, when results of the Phase 3 multicenter trial in hemodialysis patients were published.11 The dose of erythropoietin required for maintaining the hematocrit between 32% and 38% in this study varied over 20-fold among trial subjects. In the succeeding decades, the range of ESA dosages used in clinical practice expanded, and there is now a more than 100-fold difference in ESA doses utilized across the spectrum of clinical practice in dialysis care. These findings strongly suggest that the ESA dose–response relationship is much more complex than originally conceived, with the corollary that anemia in individuals with kidney disease is far more complex and multifaceted than assumed initially. All drugs have a therapeutic index, the ratio between the dose required for efficacy versus toxic effects, and biologically potent agents such as ESAs, which have pleiotropic effects, are particularly likely to have potential toxicity. Yet the current paradigm in the treatment of anemia is still solely to treat to a target range of hemoglobin concentrations irrespective of dose. With a specific range in mind, the health care provider titrates the ESAs, as needed, in attempting to reach that target. Since the only measure of success is achieving the target, there is little or no concern for potential toxicity or establishing a therapeutic index. Despite the continuing “monotonic paradigm” for ESA dosing, factors related to intercurrent illness and comorbidities that are outside of the physician's control and are often not measurable in clinical practice frequently prevent reaching the target hemoglobin concentration. Although speculative, we hypothesize that the toxic effect of high-dose ESAs may be most concerning in the subset of ESA-resistant patients, who paradoxically receive the highest ESA doses to achieve hemoglobin concentration targets. It is now well recognized that the high prevalence of increased inflammation and oxidative stress in patients with mild, moderate, or dialysis-dependent CKD, along with iron deficiency, are the major identifiable factors associated with ESA resistance.12,13 Among other operative mechanisms by which oxidative stress and inflammation influence anemia, increased oxidation of erythrocyte membrane phospholipids shortens erythrocyte lifespan, whereas inflammation induces expression of hepcidin, thereby blocking egress and mobilization of storage iron into hematopoietic precursor cells. Furthermore, increased inflammation and oxidative stress are closely associated with high rates of cardiovascular complications in CKD and dialysis patients. It is also now clear that biologically active erythropoietin receptors exist in a variety of tissues outside the hematopoietic system, whose activation may lead to toxicity. Engagement of erythropoietin receptors in the vasculature can lead to upregulation of endothelin-1 production, increase the release of vasoconstrictive prostanoids, including thromboxane and prostaglandin F2-alpha, and upregulate gene expression of multiple angiotensin-II-responsive genes, including TGFβ, platelet-derived growth factor, and epithelial growth factor.14–16 Erythropoietin increases growth of vascular smooth muscle and endothelial cells in a dose-dependent manner in vitro, which may contribute to vascular disease progression in vivo.17,18 Several studies implicate ESAs in activating thrombogenic pathways by increasing tissue factor expression, plasma thrombomodulin levels, and platelet count and activation through transactivation of thrombopoietin receptors.19,20 In one study, erythropoietin increases plasma levels of asymmetric dimethylarginine, a competitive substrate for nitric oxide synthase. Higher plasma asymmetric dimethylarginine levels are associated with adverse cardiovascular outcomes in CKD. Although there are multiple mechanisms for high-dose ESAs to augment the already high cardiovascular risk in patients with kidney disease, careful studies focusing on dose-dependent toxicology are not available. The hypothesis that use of high-dose ESAs have toxicity and are not just a surrogate for morbidity and mortality associated with erythropoietin resistance is consistent with a recent post hoc analysis of the CHOIR study.21 Here, landmark analyses assess the relationship among achieved hemoglobin concentration (≥13.1 g/dl in high-hemoglobin or ≥11.1 g/dl in low-hemoglobin arms), high-dose erythropoietin (≥20,000 units/wk), and the primary composite endpoint (death, myocardial infarction, congestive heart failure, or stroke). In the 4-mo landmark analysis, far more subjects in the high-hemoglobin versus low-hemoglobin arm were unable to achieve the target hemoglobin concentration (37.5% versus 4.7%) and required high-dose erythropoietin (35.1% versus 9.6%). In adjusted models, high-dose erythropoietin associates with a 57% increased hazard of the primary endpoint (hazard ratio of 1.57, confidence interval of 1.04 to 2.36), whereas the risk associated with randomization to the high-hemoglobin arm is NS (P = 0.49), suggesting possible mediating effects of a higher target concentration by dose. Similar results are observed in the 9-mo landmark analysis. This analysis supports the hypothesis that high-dose erythropoietin is more than a marker of inflammation and may partially explain increased risk with high-hemoglobin targets. If the hypothesis that high-dose ESAs have direct cardiovascular toxicity is substantiated, then the problem is not “treating to a higher hemoglobin,” which is biologically beneficial, but instead “using high-dose ESAs in an effort to achieve a higher hemoglobin,” where adverse effects of ESAs outweigh benefits from a higher hemoglobin concentration. Although this may seem a subtle distinction, the clinical consequences are profound. Where would this lead us? First, prospective studies should confirm these relationships and determine the safest dosing algorithms. Perhaps a fixed-dose strategy of ESA use should be compared with titration algorithms in a randomized trial. The biologic mechanism underlying potential toxic effects of ESAs has to be more thoroughly defined, including examination of dose-dependent, nonhematopoietic effects in subjects with different levels of ESA resistance. On an individual patient level, those who can reach higher hemoglobin levels without requiring high-dose ESAs should be allowed to enjoy this benefit. Patients feel better at higher hemoglobin concentrations, and exercise tolerance and quality of life are better. The key subgroup of ESA-resistant patients who do not respond to moderate doses of ESA will need completely different treatment goals and strategies. Novel strategies targeting a reduction in ESA resistance, thereby allowing attainment of higher hemoglobin concentrations without resorting to high-dose ESAs, should be prioritized for this group. But for those who remain ESA-resistant, the answer might be to adopt the concept of “permissive anemia,” similar to permissive hypercapnia in the management of respiratory failure. This would require changing the paradigm of benchmarks under which we have operated for nearly 20 yrs. DISCLOSURES None.